Disulfide-linked protein aggregates (green) in both the cytosol and nuclei (blue) of mouse hippocampal neurons
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Dr. Robert C. Cumming
Redox Proteomics and Cell Biology
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Position: Assistant Professor Office: BGS 3078 Fax: 519 661-3935 Email: rcummin5@uwo.ca |
Research Statement
Redox Regulation of Proteins Involved in Ageing and Disease
Reactive oxygen species (ROS) are involved in a variety of different cellular processes including cytokine mediated signalling, apoptosis, cell proliferation and ageing. Although ROS have traditionally been perceived as agents that cause non-specific damage to biological macromolecules it is now known that ROS selectively modify a wide spectrum of proteins. ROS mediated oxidation of protein cysteine sulfhydryl groups (Cys-SH) can lead to the formation of covalent disulfide bonds (Cys-S-S-Cys). Although disulfide bond formation in eukaryotes has generally been studied in the context of cell surface or secreted proteins that fold within the endoplasmic reticulum, recent studies suggest that disulfide bond formation occurs within multiple subcellular environments including the cytosol, mitochondria and the nucleus. However, the effect of disulfide bonding on the function, stability and intracellular transport of many redox sensitive proteins is just now being explored. In addition, cells that primarily use glycolysis to meet cellular energy requirements, exhibit decreased ROS production and resistance to apoptosis. Research in my lab focuses on the effect of altered metabolism and associated redox modifications of proteins implicated in several age-related disorders, including Huntington’s disease (HD), Alzheimer’s disease (AD) and cancer. Current projects include:
1) Identification of redox sensitive proteins in Huntington’s disease cell models . Oxidative stress has been implicated in HD, an inherited neurodegenerative disorder characterized by the intracellular accumulation of a polyglutamine containing protein (Huntingtin) and the progressive loss of striatal neurons. Preliminary studies in my lab have shown that overexpression of pathogenic Huntingtin in nerve cell lines promotes oxidative stress and increased disulfide bonding of cytoplasmic, mitochondrial and nuclear proteins. The redox status of these proteins, many of which have antioxidant functions, are currently being characterized in different HD cell models. In addition, several thiol-based antioxidant compounds are being tested for their ability to prevent mutant Huntingtin induced disulfide bond formation and toxicity.
2) Exploring the role of increased glycolytic metabolism in amyloid-beta resistant nerve cells. Accumulation of the amyloid-beta peptide within the brain tissue of AD patients is strongly linked to oxidative stress and neurotoxicity. Nerve cell lines that are resistant to amyloid-beta toxicity display enhanced glycolysis. Projects in my lab examine different glycolytic enzymes and their ability to influence cellular antioxidant defence and resistance to amyloid-beta. Understanding the role that glycolysis plays in amyloid-beta resistant nerve cells can provide novel insight into AD pathogenesis.
3) Evaluating the effect of elevated glycolysis on the disulfide proteome of breast cancer cells. Breast cancer cells exhibit elevated levels of glycolytic enzymes and the increased production of lactic acid compared to non-transformed cells. This altered metabolism, strongly associated with cancer, also has profound effects on the redox status of cells. Several proteomic based projects in my lab examine the type of intracellular and extracellular disulfide-linked proteins that are altered in breast cancer cells. Identification of disulfide bonded proteins that are unique to breast cancer cells may reveal novel targets for therapy.
